1. Field of the Invention
The present invention is related to the fields of neuropharmacological agents, including agents that are useful in the treatment of attention deficit hyperactivity disorder and multiple sclerosis associated fatigue.
2. Description of Related Art
Attention-deficit/hyperactivity disorder (ADHD) is a chronic neuropsychiatric disorder in children that is characterized by developmentally inappropriate hyperactivity, impulsivity, and inattention. ADHD is estimated to affect 3%–5% of school-age children. Historically ADHD was thought not to continue beyond adolescence; however, current research suggests that ADHD persists into adulthood in 10% to 60% of childhood-onset cases. ADHD persistence is associated with a high incidence of academic and occupational dysfunction, as well as a high incidence of psychiatric comorbidity (e.g., conduct, major depressive, and anxiety disorders). It is estimated that approximately 1% to 3% of adults have symptoms of ADHD. Adults with ADHD have a pattern of demographic, psychosocial, psychiatric, and cognitive features that mirrors well-documented findings among children with the disorder. This further supports the validity of the diagnosis for adults. The core ADHD symptoms in adults include a frequent and persistent pattern of inattention/distractibility and/or hyperactivity-impulsivity. The most common symptoms exhibited in ADHD adults are marked inattention, poor concentration, easy distractibility, day dreaming, forgetfulness and a frequent shift in activities. ADHD adults also report marked impulsivity, intrusiveness, low frustration/stress tolerance, temper tantrums, irritability, and extreme impatience. Less commonly reported symptoms in adults include hyperactivity, which may be confined to fidgeting, or an inward feeling of jitteriness or restlessness. In addition to the core ADHD symptoms, adults with ADHD often exhibit associated clinical characteristics such as boredom, social inappropriateness, and chronic conflicts in social situations. These features may be responsible for the high incidence of: (1) separation and divorce and (2) poor academic performance and occupational achievement that exist despite adequate intellectual abilities. In addition, adults with ADHD have a high incidence of substance abuse disorders.
While the pathogenesis of ADHD remains unclear, alterations in the dopaminergic and noradrenergic functions appear to be the neurochemical basis for the disorder. Brain positron emission tomography in adults with ADHD have revealed alterations in glucose metabolism in areas of the cerebral cortex that are involved with attention and motor activity, like the frontal lobe. The most common treatment for both adult and pediatric ADHD is stimulants (e.g., dextroamphetamine, methylphenidate, and pemoline). Stimulants are thought to work by increasing the amount of dopamine available in the synapses of the neuron. The stimulants appear to do this in multiple cerebral anatomical locations. Other therapies that have been used include: antidepressants (e.g., tricyclic antidepressants such as imipramine and desipramine; novel antidepressants such as buproorion and venlafaxine), antihypertensives (e.g., clonidine and guanfacine), monoamine oxidase inhibitors ([MAO's], e.g., selegiline), amino acids (e.g., levodopa, phenylalanine, and L-tyrosine), and combined pharmacotherapies (e.g., concurrent use of a serotonin-selective reuptake inhibitor and a stimulant medication; or a stimulant and catelcholaminergic antidepressant regimen) (Bhandary et al., Psychiatric Annals 27:545–555, 1997; Wilens et al., J. Clin. Psychopharmacol. 15:270–279, 1995; Finkel, The Neurologist 3:31–44, 1997; Miller and Catellanos, Pediatrics in Review 19:373–384, 1998).
While stimulants are the most commonly used treatments, approximately 30%–50% of adults with ADHD do not respond positively to the stimulants, have unacceptable side effects or have concurrent depressive or anxiety disorders that stimulant medications may exacerbate or be ineffective in treating. The long-term adverse effects and their use in high-risk substance abuse subgroups of ADHD remain unstudied and are of concern; thus, there is still a need for nonstimulant pharmacotherapy for ADHD.
Another condition for which there is a long felt need for a non-stimulant pharmacological therapy is the fatigue associated with multiple sclerosis (MS). Multiple sclerosis is one of the most common disabling neurologic diseases of young adults in the United States, where an estimated 400,000 persons have the disease. Although MS can cause a variety of disabling neurological impairments such as blindness, paralysis, incoordination, and bowel or bladder dysfunction, a less apparent symptom that can also be severely disabling is fatigue. In one study involving 656 patients with MS, 78% complained of fatigue, 60% experienced it every day, and 22% suffered disruption of their daily activities (Freal et al., Arch. Phys. Med. Rehabil. 65:135, 1984). The National Multiple Sclerosis Society evaluated 839 patients who had only minor neurologic impairment despite having bad MS for longer than 10 years, and fatigue was the most commonly reported symptom in this group of mildly affected patients (Jones, New York: National Multiple Sclerosis Society, Health Services Research Report, 1991). In another study 40% of MS patients listed fatigue as the most serious symptom of their disease (Murray, Can. J. Neurol. Sci. 12:251, 1985). Fatigue is reported to be the cause of at least temporary disability in up to 75% of patients with MS; and the British MS Society found fatigue to be the most important symptom leading to unemployment in this group (Rolak, Curr. Neurol. 9:109, 1989). In the United States, the prevalence of disability related to MS fatigue is underscored by its inclusion as a criterion for disability allowance under guidelines set forth by the Social Security Administration.
The mechanism of MS fatigue is poorly understood. It has been attributed to nerve conduction abnormalities within the central nervous system and increased energy demands caused by neurologic disability. Several characteristics of MS fatigue are interference with physical functioning and activities of daily living, aggravation by heat, and worsening at the end of the day (Krupp et al., Arch. Neurol. 45:435, 1988). Medications that are prescribed for the treatment of MS fatigue include amantadine, pemoline, and other stimulants. Amantadine has been demonstrated to benefit MS fatigue in 79% of patients in a double blind, randomized study, but its mechanism of beneficial action is not known (Krupp et al., Neurology 45:1956, 1995). Although amantadine has been demonstrated in a rigorous fashion to benefit MS fatigue, the benefit is partial for most patients and there are still significant numbers of patients who report no benefit. The same study failed to show a beneficial effect for pemoline, which is often used in the treatment of MS fatigue. There is a strong need, therefore, for a safe and effective treatment for this debilitating condition.